Evaluation of the immunoregulatory potential of the analogous one of lidocaine JMF2-1 in a murino model of asthma.
Asthma is a chronic inflammation of the lung airways caused by environmental factors in genetically predisposed individuals. Our previous study showed that nebulization of thestructural analog of lidocaine JMF2-1 might be a way of achieving the anti-asthmatic effects of lidocaine without the anesthetic effect. Since the mode of action of JMF2-1 is still unclear, we examined here its putative immunoregulatory effect in comparison to lidocaine and dexamethasone. Ovalbumin-sensitized BALB/c mice were daily nebulized with ovalbuminand treated with lidocaine or JMF2-1 aerossol concomitantly and eight hours post-challenge, from day 19 to 21 post-sensitization, being all analyses performed 24 h after the last challenge. Dexamethasone intraperitoneal treatment was done one hour before each challenge. We found that both lidocaine and JMF2-1 inhalation inhibited crucial features ofasthma including lung eosinophilia and bronchial hyperresponsiveness. Treatments with inhaled lidocaine or JMF2-1, as well as i.p. dexamethasone, inhibited IL-4, IL-5 and IL-13 secretion by cultures of lung explants obtained from mice sensitized and challenged with ovalbumin. Following a second challenge, now in vitro, IL-5 and IL-13 production wereinhibited when the explants were from dexamethasone- but not lidocaine- or JMF2-1- treated donors. Ovalbumin-evoked cytokine production by and proliferation of lymph node cells,from DO11.10 TCR transgenic mice, were inhibited by both JMF2-1, lidocaine and dexamethasone applied in vitro. Moreover, JMF2-1 and lidocaine induced apoptosis of theseT cells in vitro, detected by propidium iodide and annexin V. In all parameters assessed in vitro JMF2-1 was more efficient than lidocaine. These results show that inhalation of JMF2-1prevents cardinal features of asthma, probably by reducing Th2 cytokine generation via inhibition of T cell function and survival. JMF2-1 should be considered as a new prototype in drug discovery for asthma with advantages over local anesthetics.
Advisor:Marco Aurélio Martins
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Date of Publication:11/12/2007